Regulation of intestinal epithelial barrier function by intercellular junction proteins in health and disease

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Abstract Inflammatory bowel diseases are characterized by intestinal inflammation, increased mucosal cytokines and compromised epithelial barrier function. Epithelial barrier function is regulated by intercellular junctions that encompass the tight junction (TJ), adherens junction (AJ) and desmosomes (DMs). It is now evident that intercellular junctions are highly dynamic structures and their component proteins actively participate in regulating epithelial homeostasis. Mucosal inflammation compromises epithelial homeostatic properties thereby resulting in epithelial barrier compromise which contributes to disease pathogenesis. Our knowledge of the molecular basis of intercellular junction protein cross-talk, epithelial homeostasis and compromised barrier in intestinal inflammation is however very limited. Thus the overall goals of this proposal are to identify mechanisms by which intercellular junction proteins control epithelial homeostasis, barrier function and repair after injury in disease. We will specifically investigate the role of two key intercellular junction proteins, claudin23 and desmoglein 2 in regulating the intestinal epithelial barrier function and repair after injury. The influence of inflammatory cytokines on such regulatory processes will be determined. In addition to gaining insights into the molecular basis of intestinal epithelial barrier regulation, these studies will provide new ideas for the development of therapeutic agents that strengthen the intestinal epithelial barrier, promote wound repair and reduce mucosal inflammation. These studies will also provide insight into strategies of transiently perturbing the epithelial barrier for therapeutic drug/vaccine delivery.